76 Original Article

Stroke-Like Episodes in Propionic Acidemia Caused by
Central Focal Metabolic Decompensation

Authors

S. Scholl-Bürgi1, E. Haberlandt1, T. Gotwald2, U. Albrecht1, S. Baumgartner Sigl1, M. Rauchenzauner1,
K. Rostásy1, D. Karall1

Affiliations

1

Key words

Abstract
&

▶ propionic academia
●
▶ CSF/plasma ratio
●
▶ stroke-like episodes
●

Propionic acidemia caused by propionyl-CoA
carboxylase deficiency frequently leads to neurologic complications. Herein we report an
eleven-year-old patient with propionic acidemia
having three stroke-like episodes during a period
of 13 months characterized by acute reversible
hemiplegia and vegetative symptoms like bradycardia or drowsiness. No biochemical signs of
severe metabolic decompensation were detectable in plasma. At all three episodes, EEG was
not indicative for status epilepticus, but in the
acute episode it showed slowing of background
activity emphasized on one side. MRI revealed
reversible hyperintensities in cortical grey mat-

Abbreviations
&

received
accepted

26.03.2009
19.06.2009

Bibliography
DOI 10.1055/s-0029-1231065
Neuropediatrics 2009;
40: 76–81
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0174-304X
Correspondence
Sabine Scholl-Bürgi, MD
Medical University Innsbruck
Department of Pediatrics
Anichstraße 35
6020 Innsbruck
Austria
Tel.: + 43/512/504 23 600
Fax: + 43/512/504 25 886
sabine.scholl-buergi@uki.at

BG
CNS
CRP
CSF
FLAIR
MRI
MRS
PA

basal ganglia
central nervous system
C-reactive protein
cerebrospinal fluid
fluid-attenuated inversion recovery
magnetic resonance imaging
magnetic resonance spectroscopy
propionic acidemia

Introduction
&
Propionic acidemia (PA, MIM 606 054) is caused
by a deficiency of propionyl-CoA carboxylase
(PCC) (EC 6. 4.1.3). PCC is a mitochondrial enzyme
that catalyzes the ATP-dependent carboxylation
of propionyl-CoA to d-methylmalonyl-CoA. Propionyl-CoA is produced by catabolism of the
amino acids isoleucine, methionine, threonine,
valine, the odd-chain fatty acids, the pyrimidines
thymine and uracil and cholesterol [5].

Scholl-Bürgi S et al. Stroke-Like Episodes in Propionic Acidemia … Neuropediatrics 2009; 40: 76–81

ter and basal ganglia. During the third episode
a lumbar puncture was done in parallel with
venous puncture. Concentrations of glutamine
(902 μmol/L), glycine (24 μmol/L) and alanine
(78 μmol/L) were elevated in CSF. In plasma
glycine (1 859 μmol/L) and alanine (608 μmol/L)
concentrations were also elevated, whereas
the glutamine (458 μmol/L) concentration was
normal. CSF/plasma ratios were elevated for
glutamine (1.97) and alanine (0.13) and normal
for glycine (0.01). We assume that the strokelike episodes in our patient may be caused by an
acute focal cerebral metabolic decompensation,
which is detectable by unspecific changes in MRI
and by measuring amino acids and lactate in CSF
versus plasma.

Most patients with PA present in the newborn
period with severe metabolic acidosis manifesting as feeding difficulties, episodic vomiting,
lethargy and muscular hypotonia. Seizures, dehydration and hepatomegaly occur less frequently
during the early period [16, 25].
MRI in PA patients shows delayed myelination,
cerebral atrophy with an enlarged ventricular
system and subarachnoidal spaces and changes
in the basal ganglia to a variable degree [2–4]. In
MRS a decrease of N-acetylaspartate and myoinositol and an elevation of glutamine/glutamate/
GABA (Glx peak) in basal ganglia were detectable
even in metabolically stable situations [2].
After the first derangement, the neurological
outcome is often poor [22] and mental retardation to a varying degree is a common feature in
PA, especially in patients with early onset of the
disorder [15, 22–24]. Additionally, the patients
suffer from movement disorders without measurable changes in neurotransmitter concentrations in CSF [22] and seizures are reported
frequently in PA patients [9, 25]. Acute infantile
hemiplegia after seizures was reported only in a

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Innsbruck Medical University Innsbruck, Department of Pediatrics IV, Division of Neuropediatrics and Inherited Metabolic
Disorders, Innsbruck, Austria
2
Innsbruck Medical University Innsbruck, Department of Radiology II, Innsbruck, Austria

Original Article 77

Episode

One

Two

Three

age
weight (kg)
height (m)
therapy

9y9m
31 (P50)
1.31 (P10)
+
12 g per day

10 y 7 m
33 (P50)
1.33 (P10)
+
12 g per day

10 y 10 m
33 (P25–50)
1.34 (P3–10)
+
12 g per day

2 000
levetiracetam therapy
(start)
drowsiness, vomiting,
weakness left arm
and leg
day two
positive
cortical positive, BG
positive
cortical positive, BG
positive
normal
normal
not available
day two
coma acitivity (predominatly on the right
side)

2 000
levetiracetam (30 mg
per kg bw)
drowsiness, weakness left side,
bradycardia

2 000
levetiracetam (30 mg per
kg bw)
drowsiness, low temperature, one week before:
weakness of right side
day one
slightly positive
cortical normal, BG
slightly positive
cortical normal, BG
slightly positive
normal
Normal
not available
day one
both sides 8–10/s
(wake), right side 3/s, left
side 1–1.5/s (drowsiness)

protein defined nutrition
precursor free amino
acid mixture
L-carnitine (mg per day)
medication

symptoms

MRI
diffusion
PD/T2-weighted
FLAIR
T1-weighted − / + Gd
MR angiogram
spectroscopy
EEG
background activity

epileptiformic discharges

control (three weeks later)
normal
cortical normal, BG slightly
positive
cortical normal, BG slightly
positive
normal
normal
not available

not detectable

ten-month-old girl with PA. The hemiplegia lasted for three
months [19].
We report an eleven-year-old female patient with propionic
acidemia who had three episodes with acute hemiparesis and
vegetative symptoms like drowsiness and bradycardia within a
period of 13 months.

Patient and Methods
&
The patient is an Austrian girl in whom clinical symptoms began
at age 3 days with tachypnea, feeding difficulties and lethargy.
Diagnosis was established at age 5 days by determination of
organic acid excretion in urine. Propionyl-CoA carboxylase activity was reduced and the diagnosis was later confirmed by demonstration of homozygosity for the mutation IVS 11-2A > G in the
PCCB gene of propionyl-CoA carboxylase [14]. She was treated
with a protein-defined diet (actually 1.3 g/kg/d) supplemented
with l-carnitine and an amino acid preparation excluding
▶ Table 1).
methionine, threonine, valine and isoleucine (●
Between ages 9 and 10 years she had three stroke-like episodes
without apparent metabolic decompensation.
At the first episode the patient was 9 years and 9 months old,
clinical symptoms were sudden onset of drowsiness, vomiting
and weakness of the left arm and leg. There was no infection
detectable and no signs of catabolism. Routine laboratory results
showed only slightly elevated ammonia and lactate concentrations
▶ Table 2).
and were otherwise normal (including CSF results, ●

day three
right side 3–4/s, left
side 5–7/s (wake),
right side 2–3/s, left
side 5/s (drowsiness)
spike-waves temporo-parieto-occpital
on both sides with
secundary generalization

spikes and spike-slowwave 3/s on the left side
occipital and on the right
side central

Plasma amino acid analysis showed elevated concentrations of
proline, glycine, alanine and lysine and decreased concentra▶ Table 3). A CT scan was normal (on day
tions of isoleucine (●
one), a cerebral MRI scan at day two of hospitalization showed
slightly hyperintense basal ganglia on both sides and hyperintense cortical grey matter on the right temporal side on diffu▶ Table 1, ●
▶ Figs. 1a, b). A
sion and FLAIR imaging sequences (●
control MRI three weeks later showed an improvement of the
▶ Table 1, ●
▶ Figs. 1c, d). EEG was done on
previous findings (●
day two of hospitalization (conducted under general anaesthesia for MRI scan) and showed slowing of background activity
▶ Table 1, ●
▶ Fig. 2a). Later in the
emphasized on the right side (●
course, spike-waves on the central area on the left side were
▶ Fig. 2b). Therefore, therapy with levetiracetam
detectable (●
(with increasing dose of 30 mg per kg body weight) was started
because a possible non-convulsive status or seizure could not be
ruled out at that time.
At age 10 years and 7 months she again developed an acute
hemiparesis of the left side, drowsiness, had a bradycardia (down
to 40/min) and low body temperature (35.7 ° C). Routine labora▶ Table 2). Plasma
tory results on admission were normal (●
amino acid analysis showed elevated proline, glycine and alanine
▶ Table 3). In EEG on day three a slowing especoncentrations (●
cially of the right side and spike waves temporo-parieto-occipi▶ Table 1). A cerebral MRI
tal on both sides were detectable (●
scan was not performed.
One week before the last admission to hospital, at age 10 years
and 10 months, the patient had vegetative symptoms like low

Scholl-Bürgi S et al. Stroke-Like Episodes in Propionic Acidemia … Neuropediatrics 2009; 40: 76–81

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Table 1 Clinical, EEG and MRI findings on three occasions in a PA patient with acute hemiplegia and vegetative symptoms.

78 Original Article

episode one, day two

b

episode one, control

c

episode three, day one

e

d

Fig. 1 MRI scans at episode one and three (diffusion and FLAIR imaging) showing abnormal hyperintense signal of cortex and basal ganglia. Diffusion (a)
and FLAIR (b) imaging, abnormal hyperintense signal of cortex and basal ganglia (arrows). Diffusion (c) and FLAIR (d) imaging, normalization of hyperintense
signal of cortex and basal ganglia (arrows). FLAIR imaging (e), abnormal hyperintense signal of cortex (arrows).

body temperature and paleness and additionally weakness of
the right side twice. These symptoms lasted for a maximum of
two hours. On the day of last admission to hospital the mother
reported that the girl suddenly became pale, was whining and
laid down. The body temperature was low (35.7 ° C) and subsequently she vomited once. On admission (at 2 pm) ammonia
concentration in plasma was slightly elevated (196 μmol/L),
whereas the other routine laboratory results were again normal
▶ Table 2). In the evening a lumbar
including blood gas analysis (●
puncture was done (at 8 pm). The patient had her last meal more
than six hours before, but was receiving glucose infusion (6 g/kg
b. w. per day). In CSF, an elevated lactate concentration
▶ Table 2). Amino acid concentra(5.2 mmol/L) was detectable (●
▶ Table 3 (note: CSF was
tions in plasma and CSF are shown in ●
free of erythrocytes). EEG again showed slowing of background
activity emphasized of the left side and temporo-parieto-occipital spike-waves on both sides accentuated on the right side
▶ Table 1, ●
▶ Figs. 2c, d). An MRI scan showed hyperintense
(●
cortical grey matter in FLAIR imaging and slightly hyperintense

▶ Table 1, ●
▶ Fig. 1e). Clinical sympbasal ganglia on both sides (●
toms resolved completely within the next day without a specific
therapy.

Discussion
&
Our patient had three episodes of acute hemiplegia and vegetative symptoms like bradycardia, low body temperature and
drowsiness. These episodes can be interpreted as stroke-like
episodes. Despite frequent reports on neurological outcome in
PA patients, acute hemiplegia or stroke-like episodes are rarely
reported. Stroke-like episodes are focal cerebral disturbances
not primarily due to a vascular insufficiency, resulting in a focal
neurological deficit that is persistent but can also recover [12].
They can occur in mitochondriopathies [13] and other inborn
errors of metabolism [21]. Mechanisms for stroke-like episodes
with focal neurological signs, beside others, include perfusion
abnormalities and accumulation of toxic metabolites [21].

Scholl-Bürgi S et al. Stroke-Like Episodes in Propionic Acidemia … Neuropediatrics 2009; 40: 76–81

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a

Original Article 79

episode one, day two, patient under general anesthesia

Fig. 2 EEG investigations a: slowing of
background activity emphasized on the right side;
b: slowing of background activity emphasized on
the right side, spike-waves central area left side
with tendency of generalization.

10 s/page, sensitivity 10 µV/mm, filter: LF 0.5/HF 70, Notch 50 Hz

b

episode one, day three, patient awake

10 s/page, sensitivity 15 µV/mm, filter: LF 0.5/HF 70, Notch 50 Hz

In our patient severe metabolic decompensation was not detectable in plasma. MRI showed discrete changes of cortical grey
matter on one side and additional changes in basal ganglia on
both sides. EEG showed asymmetric slowing of background
activity indicating focal metabolic changes. In the third episode
a lumbar puncture was done in parallel with venous puncture.
Interestingly, glutamine and lactate concentrations in plasma
were normal, but in CSF elevated. Consequently, the CSF/plasma
ratios of these metabolites were elevated. Additionally, alanine
concentrations in CSF and plasma and CSF/plasma ratio were
slightly elevated, whereas glycine concentrations were elevated
in CSF and plasma, but not CSF/plasma ratio − as has already
been shown in other PA patients [17]. The elevation of alanine,
lactate and glutamine concentrations in CSF indicate cerebral
production and trapping of metabolites as a cause (or result) of
neurological symptoms. In addition, Kölker et al. [10] hypothesized that the limited efflux of dicarboxylic acids produced in
CNS of patients with organic acidurias leads to neurological
symptoms. We showed that in our patient this is true even for
secondary elevated metabolites like alanine, lactate and

glutamine, where the elevated CSF/plasma ratios indicate trapping in CNS. This is a hint at significant stress-induced amino
acid catabolism in the brain caused by cerebral production of
organic acids as hypothesized by Morris [11].
Interestingly, plasma glutamine concentrations in PA patients
are normal even during hyperammonemia [6]. This may be
caused by “inability to maintain adequate levels of glutamine
precursors through a dysfunctional Krebs cycle” [6]. In metabolically stable situations, CSF glutamine concentrations can be
normal, but in MRS the Glx peak (glutamine, glutamate and
some GABA) in brain tissue is elevated [2]. Glutamine can be
synthesized from glutamate and ammonia catalyzed by
glutamine synthetase, an astroglia-specific enzyme. Glutamine
is a non-toxic ammonia carrier within the CNS and additionally
it is an idiogenic osmolyte leading to astrocytic swelling [1].
Mechanisms which lead to glutamine synthesis in CNS in our
patient are unclear, as ammonia in plasma was not massively
elevated at the time of admission. However, one could speculate
that this was the case before admission and therapy with the “at

Scholl-Bürgi S et al. Stroke-Like Episodes in Propionic Acidemia … Neuropediatrics 2009; 40: 76–81

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a

80 Original Article

episode three, day one, patient asleep

d

episode three, day one, patient asleep

Fig. 2 (Continued) c: slowing of background
activity emphasized on the left side; d: slowing of
background activity emphasized on the left side,
spike-waves on the occipital area of the right side
with generalization.

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c

10 s/page, sensitivity 15 µV/mm, filter: LF 0.5/HF 70, Notch 50 Hz

10 s/page, sensitivity 15 µV/mm, filter: LF 0.5/HF 70, Notch 50 Hz

Table 2 Laboratory findings on three occasions in a PA patient with acute hemiplegia and/or vegetative symptoms.
Episode

One

Two

Three

age
laboratory investigations
blood

9y9m
day one
3.3
26
18
17
pH 7.38
92
4.2
4 900
70.1
105 000
10.7
0
271
4.7
n. d.

10 y 7 m
day one
4.8
25
45
26
pH 7.32
70
2.4
4 600
79.4
86 000
4.7

10 y 10 m
day one
3.2
36
32
17
pH 7.43
196
2.1
5 800
73.8
129 000
8.7
0
215
3.8
5.2

CSF

urea (mmol/L)
creatinine (μmol/L)
GOT (U/L)
GPT (U/L)
blood gases
ammonia (μmol/L)
lactate (mmol/L)
leukocytes (per μL)
hemoglobin (mmol/L)
thrombocytes (per μL)
CRP (mg/L)
leukocytes (per μL)
protein (mg/L)
glucose (mmol/L)
lactate (mmol/L)

(n. d. = not determined)

Scholl-Bürgi S et al. Stroke-Like Episodes in Propionic Acidemia … Neuropediatrics 2009; 40: 76–81

Original Article 81

Table 3 Amino acid concentrations in plasma and CSF and CSF/plasma ratio in a PA patient with reference values in brackets (amino acid concentrations were
determined as previously described [18], values in bold elevated concentrations, cursive decreased values; plasma reference values are indicated only once, for
plasma reference values see [8,20], for CSF reference values see [7,20] (* reference value for CSF proline is taken from [18]) and for CSF/plasma ratios see [18]
(CSF/plasma ratio glutamate is not available, n.a.))
episode two

day one

day three

plasma (μmol/L)

plasma (μmol/L)

plasma (μmol/L)

CSF (μmol/L)

CSF/plasma ratio

355
18
245
1 178
541
52
19
68
59
62
189
43

317
56
256
1 217
357
97
42
76
45
34
256
38

458 (333–809)
96 (14–78)
566 (40–332)
1 859 (107–343)
608 (120–600)
124 (132–480)
52 (6–122)
178 (30–246)
126 (19–119)
88 (26–98)
455 (66–270)
96 (12–112)

902 (334–658)
0.3 ( < 8.3)
3 (1.5–7.9)*
24 (2.9–7.9)
78 (11.1–29.6)
8 (7.6–18.0)
2 (2.2–6.2)
20 (5.4–15.4)
27 (4.3–11.7)
23 (0.5–15.9)
62 (9.1–25.5)
19 (11.3–29.5)

1.97 (0.57–1.28)
0.00 (n.a.)
0.01 (0.01–0.06)
0.01 (0.00–0.05)
0.13 (0.04–0.13)
0.06 (0.05–0.11)
0.04 (0.03–0.11)
0.11 (0.08–0.18)
0.22 (0.13–0.30)
0.26 (0.12–0.28)
0.14 (0.09–0.33)
0.20 (0.00–0.75)

home unwell-regime” was successful in decreasing ammonia
levels in the periphery but not in the CNS.
Metabolites like alanine and lactate indicate that brain energy
metabolism − especially oxidative phosphorylation − is disturbed. Alanine can be synthesized from pyruvate by accepting
an amino group from glutamate by an alanine aminotransferase
reaction. Pyruvate can additionally be reduced to lactate by
accepting electrons from NADH.
We assume that the stroke-like episodes in our patient may be
caused by an acute focal cerebral metabolic decompensation,
which causes detectable unspecific changes in MRI and can be
demonstrated by measuring amino acids and lactate in CSF versus plasma. We conclude that these investigations are useful for
the diagnosis of stroke-like episodes in patients with inborn disorders of metabolism.

References
1 Albrecht J, Doliñska M. Glutamine as a pathogenic factor in hepatic
encephalopathy. J Neurosci Res 2001; 65: 1–5
2 Bergmann AJIW, Van der Knaap MS, Smeitink JAM et al. Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia:
clinical and biochemical considerations. Ped Res 1996; 40: 404–409
3 Brismar J, Ozand PT. CT and MR of the brain in disorders of propionate and methylmalonate metabolism. AJNR 1994; 15: 1459–1473
4 Chemelli AP, Schocke M, Sperl W et al. Neonatal-onset propionic
acidemia: neurologic and developmental profiles, and implications for
management. J Magn Reson Imag 2000; 11: 596–600
5 Fenton WA, Gravel RA, Rosenberg DS. Disorders of propionate and
methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly W, Valle
D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th
edn. New York: McGraw-Hill; 2001; 2165–2190
6 Filipowicz HR, Ernst SL, Ashurst CL et al. Metabolic changes associated
with hyperammonemia in patients with propionic acidemia. Mol Gen
Metab 2006; 88: 123–130
7 Gerrits GP, Trijbels FJ, Monnens LA et al. Reference values for amino
acids in cerebrospinal fluid of children determined using ion-exchange
chromatography with fluorimetric detection. Clin Chim Acta 1989;
182: 271–280
8 Gregory DM, Sovetts D, Clow CL et al. Plasma free amino acid values
in normal children and adolescents. Metabolism 1986; 35: 967–969
9 Haberlandt E, Trinka E, Zimmerhackl LB et al. EEG-alterations in
patients with propionic acidemia. Neuropediatrics 2004; 35: 84

episode three
day one

10 Kölker S, Sauer SW, Surtees RA et al. The aetiology of neurological
complications of organic acidaemias-a role for the blood-brain barrier.
J Inherit Metab Dis 2006; 29: 701–704
11 Morris AAM. Commentary on: The aetiology of neurological complications of organic acidaemias – a role for the blood-brain barrier Kölker
S, Sauer SW Surtees RA, Leonard JV. J Inherit Metab Dis 2006; 29:
705–706
12 Pavlakis SG, Kingsley PB, Bialer MG. Stroke in children: genetic and
metabolic issues. J Child Neurol 2000; 15: 308–315
13 Pavlakis SG, Phillips PC, DiMauro S et al. Mitochondrial myopathy,
encephalopathy, lactic acidosis, and strokelike episodes: a distinctive
clinical syndrome. Ann Neurol 1984; 16: 481–488
14 Pérez B, Desviat LR, Rodríguez-Pombo P et al. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Mol Genet Metab 2003; 78: 59–67
15 Pérez-Cerdá C, Merinero B, Rodríguez-Pombo P et al. Potential relationship between genotype and clinical outcome in propionic acidaemia
patients. Eur J Hum Genet 2000; 8: 187–194
16 Sass JO, Hofmann M, Skladal D et al. Propionic acidemia revisited − A
workshop report. Clin Pediatr 2004; 43: 837–843
17 Scholl-Bürgi S, Korman SH, Applegarth DA et al. The relation of cerebrospinal fluid and plasma glycine levels in propionic acidaemia, a ‘ketotic
hyperglycinaemia’. J Inherit Metab Dis 2008; 31: 395–398
18 Scholl-Bürgi S, Haberlandt E, Heinz-Erian P et al. Determination of
amino acid CSF/plasma-ratios by ion-exchange chromatography with
ninhydrin-detection in children: influence of age and usefulness for
clinical purposes. Pediatrics 2008; 121: e920–926
19 Shigematsu Y, Mori I, Nakai A et al. Acute infantile hemiplegia in a
patient with propionic acidaemia. Eur J Pediatr 1990; 149: 659–660
20 Shih VE. Amino acid analysis In: Blau N, Duran M, Blaskovic ME, Gibson
KM, eds. Physician’s guide to the laboratory diagnosis of metabolic
diseases. 2nd edn. Berlin, Heidelberg, New York: Springer; 2003;
11–26
21 Sperl W, Felber S, Skladal D et al. Metabolic stroke in carbamyl phosphate synthetase deficiency. Neuropediatrics 1997; 28: 229–234
22 Surtees RAH, Matthews EE, Leonard JV et al. Neurologic outcome of
propionic academia. Pediatr Neurol 1992; 8: 333–337
23 Touati G, Valayannopoulos V, Mention K et al. Methylmalonic and propionic acidurias: Management without or with a few supplements of
specific amino acid mixture. J Inherit Metab Dis 2006; 29: 288–298
24 Van der Meer SB, Poggi F, Spada M et al. Clinical outcome and longterm management of 17 patients with propionic acidaemia. Eur
J Pediatr 1996; 155: 205–210
25 Wolf B, Hsia YE, Sweetman L et al. Propionic acidemia: A clinical
update. J Pediatr 1981; 99: 835–846

Scholl-Bürgi S et al. Stroke-Like Episodes in Propionic Acidemia … Neuropediatrics 2009; 40: 76–81

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glutamine
glutamate
proline
glycine
alanine
valine
isoleucine
leucine
tyrosine
phenylalanine
lysine
arginine

episode one